Sonja E. Steigen

Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts.

BACKGROUND The risk of recurrence of gastrointestinal stromal tumour (GIST) after surgery needs to be estimated when considering adjuvant systemic therapy. We assessed prognostic factors of patients with operable GIST, to compare widely used risk-stratification schemes and to develop a new method for risk estimation. METHODS Population-based cohorts of patients diagnosed with operable GIST, who were not given adjuvant therapy, were identified from the literature. Data from ten series and 2560 patients were pooled. Risk of tumour recurrence was stratified using the National Institute of Health (NIH) consensus criteria, the modified consensus criteria, and the Armed Forces Institute of Pathology (AFIP) criteria. Prognostic factors were examined using proportional hazards and non-linear models. The results were validated in an independent centre-based cohort consisting of 920 patients with GIST. FINDINGS Estimated 15-year recurrence-free survival (RFS) after surgery was 59·9% (95% CI 56·2-63·6); few recurrences occurred after the first 10 years of follow-up. Large tumour size, high mitosis count, non-gastric location, presence of rupture, and male sex were independent adverse prognostic factors. In receiver operating characteristics curve analysis of 10-year RFS, the NIH consensus criteria, modified consensus criteria, and AFIP criteria resulted in an area under the curve (AUC) of 0·79 (95% CI 0·76-0·81), 0·78 (0·75-0·80), and 0·82 (0·80-0·85), respectively. The modified consensus criteria identified a single high-risk group. Since tumour size and mitosis count had a non-linear association with the risk of GIST recurrence, novel prognostic contour maps were generated using non-linear modelling of tumour size and mitosis count, and taking into account tumour site and rupture. The non-linear model accurately predicted the risk of recurrence (AUC 0·88, 0·86-0·90). INTERPRETATION The risk-stratification schemes assessed identify patients who are likely to be cured by surgery alone. Although the modified NIH classification is the best criteria to identify a single high-risk group for consideration of adjuvant therapy, the prognostic contour maps resulting from non-linear modelling are appropriate for estimation of individualised outcomes. FUNDING Academy of Finland, Cancer Society of Finland, Sigrid Juselius Foundation and Helsinki University Research Funds.

Gastrointestinal stromal tumors with internal tandem duplications in 3' end of KIT juxtamembrane domain occur predominantly in stomach and generally seem to have a favorable course.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs express KIT and have KIT mutations. Majority of these mutations cluster in the 5′ end of the KIT juxtamembrane domain. Little is known about the clinicopathological profile of GIST carrying internal tandem duplications in the 3′ end of KIT juxtamembrane domain (ITDs in the 3′ KIT-JM). In this study, 500 immunohistochemically KIT-positive GISTs were screened for this type of mutation, and 18 cases were identified (3.6%). The majority of the ITDs consisted of 1 to 18 codon duplications, with Tyr578, Asp579, and Leu576 being the most commonly duplicated codons. There were 14 gastric (78%), 2 small intestinal (11%), and 2 anal (11%) primary tumors diagnosed in 12 females and 6 males with median age of 71 years. The frequency of IDTs in gastric GISTs was 6.5% and was only 0.5% in intestinal GISTs. There was a strong female predominance (79%) among the patients with gastric tumors. Histologically, 16 GISTs were spindle cell, and 2 had epithelioid morphology. The sizes of primary tumors varied from 1 to >20 cm. Based on the combination of tumor size and mitotic activity, six tumors were classified as benign or probably benign, eight as having uncertain malignant potential, and only four as malignant. Follow-up data available in 17 patients confirmed the malignant course of disease in 3 cases. Only one of the tumors classified as potentially malignant metastasized, although the follow-up was limited in some cases. In summary, the great majority of GISTs with ITDs in the 3′ KIT-JM were mitotically inactive tumors occurring predominantly in the stomach and that seemed to have a favorable course. This suggests that presence of these IDTs may define a clinicopathologically favorable subset of GISTs. The consequence of these mutations to KIT signaling should be investigated.

Mutations in gastrointestinal stromal tumors – a population‐based study from Northern Norway

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. This tumor typically expresses KIT, and has KIT or PDGFRA activating mutation. In this study we evaluated 89 GISTs diagnosed in Northern Norway during a 30‐year period. KIT exons 8, 9, 11, 13, and 17 were analyzed by PCR amplification and direct sequencing. Subsequently PDGRA exons 12, 14, and 18 were evaluated in KIT wild‐type cases. KIT mutations were found in 66 cases (75%), and PDGFRA mutations in 9 cases (10%). Most common were KIT exon 11 mutations, with 58 cases. Tumors with Kit exon 11 point mutations had a significantly better prognosis than those with deletions. There were five KIT exon 9 duplications, three exon 13 point mutations, and one point mutation in exon 17. There were nine PDGFGRA mutations: seven in exon 18 and two in exon 12. All but one PDGFRA mutant GISTs were gastric tumors with epithelioid morphology, and these tumors were on average smaller than those with KIT mutations. KIT and PDGFRA wild type was found in 15% of cases. Analysis of KIT and PDGFRA mutations is of significance for treatment with tyrosine kinase inhibitors, and may also have value when assessing the biological potential of GIST.

Presence of homozygous KIT exon 11 mutations is strongly associated with malignant clinical behavior in gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of gastrointestinal tract. GISTs range from benign indolent neoplasms to highly malignant sarcomas. Gain-of-function mutations of tyrosine kinase receptors, KIT or PDGFRA, have been identified in most GISTs. In this study, we report 36 GIST patients whose tumors had homozygous KIT exon 11 mutations detected by direct sequencing of PCR products. Loss of heterozygosity in KIT locus and other chromosome 4 loci were documented in majority of these tumors. However, fluorescence in situ hybridization with KIT locus-specific probe and chromosome 4 centromeric enumeration probe showed no evidence of KIT hemizygosity in a majority of analyzed cases. These findings are consistent with duplication of chromosome 4 with KIT mutant allele. Homozygous KIT exon 11 mutations were found in 33 primary tumors and 7 metastatic lesions. In two cases, shift from heterozygosity to homozygosity was documented during tumor progression being present in metastases, but not in primary tumors. Among primary GISTs, there were 16 gastric, 18 intestinal and 2 from unknown locations. An average primary tumor size was 12 cm and average mitotic activity 32/50 HPFs. Out of 32 tumors 29 (90.6%) with complete clinicopathologic data were diagnosed as sarcomas with more than 50% risk of metastatic disease, and 26 of 29 patients with follow-up had metastases or died of disease. An average survival time among pre-imatinib patients, who died of the disease was 33.4 months. Based on these findings, we conclude that presence of homozygous KIT exon 11 mutations is associated with malignant course of disease and should be considered an adverse prognostic marker in GISTs.

Trends in incidence and survival of mesenchymal neoplasm of the digestive tract within a defined population of Northern Norway

Population‐based incidence and survival data for gastrointestinal stromal tumor (GIST) are sparse due to the fact that GIST is a rather novel entity both clinically and pathologically, and has not been registered as a separate entity in population‐based cancer registries. The aim of the present study was to reclassify all mesenchymal tumors within a defined population of northern Norway over a time‐span of 30 years with the purpose of estimating trends of incidence and survival. One hundred and forty‐one patients with mesenchymal neoplasms of the digestive tract were identified: 102 as GISTs, 32 as leiomyomatous tumors, 4 as schwannomas, and 3 as fibromas. Incidence rates of GIST showed a significant increase over the whole period, which was not observed for the non‐GIST cases. Analysis of GIST cases showed that cases with more than 5 mitoses per 50 high power fields had an increased expected mortality 4 times that of those with fewer mitoses, and the combination of mitotic count and size of tumor can be recommended for categorizing the tumors into different risk levels. The study confirms that GIST is by far the most frequent mesenchymal neoplasm of the digestive tract and that the incidence has increased over the last 30 years.

Expression of insulin-like growth factor 2 in mesenchymal neoplasms

The insulin-like growth factor (IGF) system plays an important role in the growth and development of cells and has been implicated in oncogenesis and tumor progression. Gene expression profiling studies on limited numbers of specimens have shown high expression of IGF2, encoding the activating ligand for this system, in gastrointestinal stromal tumors (GISTs) and in synovial sarcomas. This data may have concrete clinical implications, as several reports exist of patients with GISTs suffering from severe hypoglycemia, a predicted effect of IGF2. Furthermore, new drugs targeting IGF signaling are entering clinical trials. The purpose of this study is to survey IGF2 expression at the protein level on a broad number of mesenchymal tumors representing all major diagnostic classes. By immunostaining tissue microarrays, results were obtained for 51 diagnostic categories of bone and soft-tissue tumors representing 1288 cases. Distinct membranous and/or cytoplasmic IGF2 immunoreactivity was assessed according to published criteria. Solitary fibrous tumors had the highest expression. Of 20 tumor types represented by more than 10 cases, synovial sarcomas, myxoid liposarcomas, GISTs, malignant peripheral nerve sheath tumors, chondrosarcomas, undifferentiated pleomorphic sarcomas (MFH), Ewings sarcomas and tenosynovial giant cell tumors showed high levels of expression in more than 20% of cases. Of the 445 GIST cases with clinical information, those with high expression of IGF2 had a significantly worse outcome than those with low or no expression. IGF2 protein expression among mesenchymal tumors is largely consistent with gene expression studies and suggests a potential for molecular therapy targeting the IGF signaling pathway system in these neoplasms.

Gastrointestinal stromal tumors (GISTs): a review.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms in the gastrointestinal tract, which, over the last 10 years, have emerged from a poorly understood neoplasm to a well‐defined tumor entity exhibiting particular molecular abnormalities and for which promising novel treatment modalities have been developed. GISTs probably arise from the precursor cell of the interstitial cell of Cajal, express KIT tyrosine kinase in most of the cases and harbor mutations of importance for individualized treatment. The molecular targets for therapeutic interventions are not only of importance for the treatment of GIST patients but also useful for in the development of novel drug modalities and new strategies in basic cancer therapy.

KIT and PDGFRA Mutations and the Risk of GI Stromal Tumor Recurrence

PURPOSE Mutated KIT and platelet-derived growth factor alpha gene (PDGFRA) drive GI stromal tumor (GIST) oncogenesis, but the clinical significance of their single mutations is known incompletely. PATIENTS AND METHODS We identified 11 population-based series of patients with GIST through a literature search and pooled individual data from 3,067 patients treated with macroscopically complete tumor excision. Mutation analysis was done from 1,505 tumors. We analyzed associations between KIT and PDGFRA mutations and recurrence-free survival (RFS) in the subsets in which patients were treated with surgery alone. RESULTS We identified 301 different single mutations in KIT and 33 in PDGFRA. Patients with PDGFRA mutations had more favorable RFS than those with KIT mutations (hazard ratio, 0.34; P = .004). Only one of the 35 GISTs with KIT exon 11 duplication mutations recurred. Patients with deletions of only one codon of KIT exon 11 had better RFS than those with another deletion type, and some KIT exon 11 substitution mutations (Trp557Arg, Val559Ala, and Leu576Pro) were also associated with favorable RFS. Patients with an identical mutation had greatly variable outcomes depending on the standard prognostic factors, notably, mitotic count. Commonly used risk stratification schemes tended to overestimate the risk for recurrence in subgroups with prognostically favorable mutations. CONCLUSION GISTs with an identical KIT or PDGFRA mutation may have widely varying risks for recurrence. Most of the patients with PDGFRA mutations and those with KIT exon 11 duplication mutation or deletion of one codon have favorable RFS with surgery alone and are usually not candidates for adjuvant therapy.

ROR2 is a novel prognostic biomarker and a potential therapeutic target in leiomyosarcoma and gastrointestinal stromal tumour

Soft‐tissue sarcomas are a group of malignant tumours whose clinical management is complicated by morphological heterogeneity, inadequate molecular markers and limited therapeutic options. Receptor tyrosine kinases (RTKs) have been shown to play important roles in cancer, both as therapeutic targets and as prognostic biomarkers. An initial screen of gene expression data for 48 RTKs in 148 sarcomas showed that ROR2 was expressed in a subset of leiomyosarcoma (LMS), gastrointestinal stromal tumour (GIST) and desmoid‐type fibromatosis (DTF). This was further confirmed by immunohistochemistry (IHC) on 573 tissue samples from 59 sarcoma tumour types. Here we provide evidence that ROR2 expression plays a role in the invasive abilities of LMS and GIST cells in vitro. We also show that knockdown of ROR2 significantly reduces tumour mass in vivo using a xenotransplantation model of LMS. Lastly, we show that ROR2 expression, as measured by IHC, predicts poor clinical outcome in patients with LMS and GIST, although it was not independent of other clinico‐pathological features in a multivariate analysis, and that ROR2 expression is maintained between primary tumours and their metastases. Together, these results show that ROR2 is a useful prognostic indicator in the clinical management of these soft‐tissue sarcomas and may represent a novel therapeutic target. Copyright

Diagnostic and prognostic markers for gastrointestinal stromal tumors in Norway

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in the gastrointestinal tract. The diagnosis of GIST is based on histology together with a panel of immunohistochemical markers; the most important is KIT (CD117). A total of 434 cases of GISTs were confirmed by histology and immunohistochemistry, and incorporated into tissue microarrays. Validation of histological features as well as the prognostic value of two immunohistochemical biomarkers (p16 and L1) was assessed. High mitotic rate, large tumor size, nuclear atypia, and small bowel primary site were all validated as negative prognostic factors in GISTs. Expression of p16 was significantly correlated with unfavorable prognosis, whereas L1 expression was not.